(19)
(11) EP 1 121 110 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Mention of the grant of the patent:
20.08.2003 Bulletin 2003/34

(21) Application number: 99952021.6

(22) Date of filing: 15.10.1999
(51) International Patent Classification (IPC)7A61K 31/155, A61K 31/20, A61K 31/513, A61K 33/00, A61K 31/551, A61K 31/554, A61K 31/505, A61K 31/55
// A61K33:00, A61K31:155, A61K31:55, A61K31:155, A61K31:505, A61K31:155, A61K31:20,(A61K31/155, A61P3:04)
(86) International application number:
PCT/US9924/262
(87) International publication number:
WO 0002/1522 (20.04.2000 Gazette 2000/16)

(54)

USE OF METFORMIN TO COUNTERACT WEIGHT GAIN ASSOCIATED WITH VALPROATE AND OTHER PSYCHOTROPIC MEDICATIONS

VERWENDUNG VON METFORMIN GEGEN DIE GEWICHTSZUNAHME, DIE MIT VALPROAT UND ANDERE PSYCHOTROPISCHE ARZNEIMITTEL VERBUNDEN IST

UTILISATION DE METFORMINE POUR MINIMISER LA PRISE DE POIDS ASSOCIEE A L'ADMINISTRATION DE VALPROATE ET D'AUTRES MEDICAMENTS PSYCHOTROPES


(84) Designated Contracting States:
AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

(30) Priority: 15.10.1998 US 104394 P
12.10.1999 US 416330

(43) Date of publication of application:
08.08.2001 Bulletin 2001/32

(73) Proprietors:
  • Cottingham, Elizabeth M.
    Cincinnati, Ohio 45220 (US)
  • Morrison, John A.
    Cincinnati, Ohio 45220 (US)

(72) Inventor:
  • COTTINGHAM, Elizabeth, Marie
    Cincinnati, OH 45219 (US)

(74) Representative: Müller-Boré & Partner Patentanwälte 
Grafinger Strasse 2
81671 München
81671 München (DE)


(56) References cited: : 
DE-A- 4 432 757
   
  • ABDALLAH O Y ET AL: "Preparation and evaluation of metformin hydorchloride controlled release tablets" S.T.P PHARMA, vol. 4, no. 1, 1988, pages 15-20, XP002128673
  • KARTTUNEN P ET AL: "The pharmacokinetics of metformin: a comparison of the properties of a rapid-release and a sustained - release preparation." INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY, THERAPY, AND TOXICOLOGY, (1983 JAN) 21 (1) 31-6. , XP002128674
  • PENTIKAINEN P J: "Bioavailability of metformin. Comparison of solution, rapidly dissolving tablet, and three sustained release products." INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY, THERAPY, AND TOXICOLOGY, (1986 APR) 24 (4) 213-20. , XP002128675
  • KIRK L. ET AL: "Metformin in treatment of obesity due to drugs. A negative pilot study (Danish)." NORD.PSYKIAT.T., (1974) 28/7 (533-537), XP002128676
  • LUTJENS A ET AL: "Effect of biguanide treatment in obese children." HELVETICA PAEDIATRICA ACTA, (1977 APR) 31 (6) 473-80. , XP002128677
  • PEDERSEN J ET AL: "Observations on the mechanism of increased weight loss during metformin administration in obesity." ACTA ENDOCRINOLOGICA, (1968 APR) 57 (4) 683-8. , XP002128678
  • PAOLISSO G ET AL: "Effect of metformin on food intake in obese subjects." EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, (1998 JUN) 28 (6) 441-6. , XP002128679
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] This application is based on and claims priority from U.S. provisional application no. 60/104,394, Cottingham and Morrison, filed October 15, 1998.

[0002] The present invention relates to improvements in the treatment of patients for seizure, bipolar disorders and psychoses.

BACKGROUND OF THE INVENTION



[0003] Clinical experience and published studies indicate the effectiveness of Valproate (depakote) in the treatment of seizure disorders and bipolar disorders. See, for example, Mattson, et al., Department of Veterans Affairs Epilepsy Cooperative Study No. 264: A Comparison of Valproate with Carbazapine for the Treatment of Complex Partial Seizures and Secondarily Generalized Tonic-Chronic Seizures In Adults. N. Eng. J. Med., 327: 765-771 (1992); Freeman, et al., Mood Stabilizer Combinations: A Review of Safety and Efficacy. Am. J. Psychiatry, 155: 12-21 (1998); and Verity, et al., A Multi-Center Comparative Trial Of Sodium Valproate And Carbamazepine In Pediatric Epilepsy. Developmental Medicine And Child Neurology, 37: 97-108 (1993). Use of Valproate, however, is also associated with side effects in as many as 50% of the patients taking it; these side effects include marked weight gain. Isojarvi et al., Polycystic Ovaries And Hyperandrogenism In Women Taking Valproate For Epilepsy, N. Eng. J. Med., 329: 1383-1388 (1993). Although not all patients experience this weight gain side effect, in those that do, the weight gain can be considerable, as much as 40-50 pounds. This side effect presents a number of patient issues, both medical and psychological, for the treating physician to consider. Such a marked weight gain can place a significant burden on the heart and circulatory system of the patient. In addition, particularly in-patients suffering from depression, such weight gain can hurt self-image and adversely impact the depressed state. Finally, and perhaps most importantly, such side effects can reduce patient compliance with the therapy regimen, thereby resulting in ineffective treatment for the primary disorder. Identification of a means to counteract these side effects partially or completely is, therefore, important. There is at present no way to prevent or treat obesity associated with the use of Valproate, except through behavioral changes such as increased physical activity or decreased caloric intake.

[0004] Metformin is a biguanide drug which is known to improve insulin action at the cellular level, but not affect insulin secretion. Metformin is used to treat patients with non-insulin dependent diabetes and has recently been used to treat women with polycystic ovary syndrome, a syndrome characterized by hirsutism, hyperandrogenism, and polycystic ovaries. It has not, however, been suggested for use in controlling the weight gain caused by Valproate or other psychotropic actives. See, for example, Valazquez, et al, Metformin Therapy Is Associated With A Decrease In Plasma Plasminogen Activator Inhibitor-1, Lipoprotein (a) and Immunoreactive Insulin Levels In-Patients With Polycystic Ovary Syndrome. Metabolism, 46: 454-457 (1997); Valazquez, et al, Metformin Therapy In Polycystic Ovary Syndrome Reduces Hyperinsulinemia, Insulin Resistance, Hyperandrogenism, And Systolic Blood Pressure, While Facilitating Normal Menses And Pregnancy. Metabolism, 43: 647-654 (1994); Jackson, et al., Mechanism of Metformin Action In Non-Insulin Dependent Diabetes. Diabetes; 36: 632-640 (1987); Landin, et al., Treating Insulin Resistance in Hypertension With Metformin Reduces Both Blood Pressure And Metabolic Risk Factors. J. Intern. Med.; 229: 181-187 (1991); and Nestler, et al., Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome. N. Engl. J. Med. 338: 1876-1880 (1998).

[0005] Kirk et al in Nord psykiat. T. (1974) 28/7 533-537 disclosed that metformin was not of any help in the treatment of drug-induced obesity.

SUMMARY OF THE INVENTION



[0006] The present invention relates to a pharmaceutical composition comprising a safe and effective amount of a psychotropic active selected from the group consisting of Valproate Risperdal, Lithobid, Zyprexa and Seroquel, together with a weight control active comprising a pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide in an amount safe and effective for minimizing weight gain caused by said psychotropic active in the patient taking said psychotropic active.

[0007] The present invention also encompasses the use of a pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide for manufacture of a composition for use in minimizing weight gain in a patient taking a psychotropic active selected from the group consisting of Valproate, Risperdal, Lithobid, Zyprexa and Seroquel.

DETAILED DESCRIPTION OF THE INVENTION



[0008] The present invention provides a method for minimizing weight gain in a patient taking Valproate or other selected psychotropic medications.

[0009] Valproate sodium is the sodium salt of valproic acid, designated as sodium-2-propylpentanoate. Valproate sodium (Divalproex sodium; Depakote) has the structure shown below:

It has a molecular weight of 166.2 and occurs as an essentially white and odorless, crystalline, deliquescent powder. Valproate sodium is typically prescribed for the treatment of epilepsy and other seizure disorders, as well as bipolar disorder. Valproate is typically available for administration orally in tablets or capsules (Depakote, manufactured and sold by Abbott Laboratories), and by intravenous injection (Depacon, manufactured and sold by Abbott Laboratories). Valproate is typically administered to a patient in need of such treatment at a dosage of about 20 mg/kg. Valproic acid (Depakene) also has associated weight gain side effects. As used herein, "Valproate" is intended to include valproic acid and its pharmaceutically-acceptable salts.

[0010] Other psychotropic actives that have an associated weight gain side effect may also be used in the present invention (i.e., they may be administered in combination with Metformin to reduce the weight gain side effect). Examples of such psychotropic actives include Risperdal (Risperidone), a medication that is prescribed for patients with psychotic disorders, tic disorders and bipolar disorder (commercially available from Janssen Pharmaceuticals); Lithobid (Lithium), a medication that is prescribed for patients with bipolar disorder (commercially available from Solvay Pharmaceuticals); Zyprexa (Olanzapine), a medication that is prescribed for patients with psychotic disorders, tic disorders and bipolar disorder (commercially available from Eli-Lilly & Company); and Seroquel (quetiapine), an anti-psychotic medication that is prescribed for patients with psychotic disorders, tic disorders and bipolar disorder (commercially available from Zeneca Pharmaceuticals). All of these actives exhibit a significant weight gain side effect with certain patients, and this side effect can be minimized using the concurrent Metformin therapy described herein.

[0011] Metformin hydrochloride is a biguanide compound that is generally prepared as an oral anti-hyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus. It is typically prepared in the form of tablets and is commercially available as Glucophage from the Bristol-Myers Squibb Company. Metformin hydrochloride (N, N- dimethylimidocarbonimidic diamide hydrochloride) has the structural formula shown below:



[0012] In addition to Metformin hydrochloride, other pharmaceutically-acceptable salts of Metformin may be used. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5.HCl, and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether or chloroform. The pKa of Metformin is 12.4. The pH of a 1% aqueous solution of Metformin hydrochloride is 6.68. Glucophage tablets contain 500mg or 850mg of Metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: povidone, magnesium stearate and hydroxypropyl methylcellulose coating.

[0013] The Metformin dosage forms used in the present invention optionally may be formulated for controlled release, sustained release, delayed release, or response release (i.e., the tablet is ingested and the active is released in response to the occurrence of a precondition in the patient, such as the intake of food by the patient, or changes in pH, sugar levels or osmolarity in the patient).

[0014] In practicing the treatment provided by the present invention, Metformin (or another pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide) is administered to a patient on Valproate therapy (or therapy with another of the psychotropic actives described above). The Valproate or other psychotropic actives will be administered using their conventional routes of administration and their conventional dosage levels. Metformin may be administered to the patient in any way known in the art, although oral administration will generally be most convenient. Metformin is administered in an amount that is safe and effective for minimizing the weight gain associated with Valproate therapy, preferably at a level of from about 1500 to about 2500 mg per day. It is typically administered with meals at a dosage of 500 mg tid.

[0015] The present invention also encompasses a combination drug that includes both Valproate or the other psychotropic actives described above, together with Metformin (including other pharmaceutically-acceptable salts of N, N-dimethylimidocarbonimidic diamide). This combination of drugs is typically formulated as a tablet or capsule for oral administration, although other routes of administration, such as intravenous injection can also be used. A tablet or capsule for oral administration of the present invention would typically include from about 250 mg to about 500mg of Valproate, and from about 250mg to about 850mg of Metformin. Conventional formulational aides, such as fillers, coatings, preservatives, disintegration aides, colorings and flavorings, can also be included at their conventional art-established levels. When the composition contains other actives, in place of Valproate, their levels per dosage typically would be as follows: Risperdal: from about 1 mg to about 4 mg; Lithobid; from about 300 mg to about 450 mg; Zyprexa: from about 2.5 mg to about 10 mg; and Seroquel: from about 25 mg to about 200 mg.

[0016] By "pharmaceutically-acceptable", as used herein, is meant that the drug-active compounds and other ingredients used in the present methods and compositions, are suitable for use in contact with the tissues of humans without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.


Claims

1. A pharmaceutical composition comprising a safe and effective amount of a psychotropic active selected from the group consisting of Valproate, Risperdal, Lithobid, Zyprexa and Seroquel, together with a weight control active comprising a pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide in an amount safe and effective for minimizing weight gain caused by said psychotropic active in the patient taking said psychotropic active.
 
2. The composition according to claim 1, wherein the weight control active is the hydrochloride salt.
 
3. The composition according to claim 2, wherein the psychotropic active is Valproate.
 
4. The composition according to any one of claims 1 to 3, which is formulated for oral administration.
 
5. The composition according to claim 4, which contains from about 250 mg to about 500 mg Valproate, and from about 250 mg to about 500 mg of the weight control active.
 
6. Use of a pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide for manufacture of a composition for use in minimizing weight gain in a patient taking a psychotropic active selected from the group consisting of Valproate, Risperdal, Lithobid, Zyprexa and Seroquel.
 
7. The use according to claim 6, wherein the pharmaceutically-acceptable salt is the hydrochloride salt.
 
8. The use according to claim 6 or 7, wherein the pharmaceutically-acceptable salt of N, N-dimethylimidocarbonimidic diamide is in a unit dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms, and response release forms.
 
9. The use according to claim 8, wherein the unit dosage form is in a response release form, wherein release of the hydrochlorid salt of N, N-dimethylimidocarbonimidic diamide is triggered by ingestion of food.
 


Ansprüche

1. Pharmazeutische Zusammensetzung, umfassend eine sichere und wirksame Menge eines psychotropen Wirkstoffs, ausgewählt aus der Gruppe, bestehend aus Valproat, Risperdal, Lithobid, Zyprexa und Seroquel, zusammen mit einem Gewichtskontrollwirkstoff, umfassend ein pharmazeutisch annehmbares Salz von N,N-Dimethylimidocarbonimid-Diamid in einer Menge, die sicher und wirksam für die Minimierung der Gewichtszunahme ist, die durch den psychotropen Wirkstoff in einem Patienten, der den psychotropen Wirkstoff einnimmt, verursacht wird.
 
2. Zusammensetzung nach Anspruch 1, wobei der Gewichtskontrollwirkstoff ein Hydrochloridsalz ist.
 
3. Zusammensetzung nach Anspruch 2, wobei der psychotrope Wirkstoff Valproat ist.
 
4. Zusammensetzung nach einem der Ansprüche 1 bis 3, die für eine orale Verabreichung formuliert ist.
 
5. Zusammensetzung nach Anspruch 4, die von etwa 250 mg bis etwa 500 mg Valproat und von etwa 250 mg bis etwa 500 mg Gewichtskontrollwirkstoff enthält.
 
6. Verwendung eines pharmazeutisch annehmbaren Salzes von N,N-Dimethylimidocarbonimid-Diamid zur Herstellung einer Zusammensetzung für die Verwendung in der Minimierung der Gewichtszunahme in einem Patienten, der einen psychotropen Wirkstoff, ausgewählt aus der Gruppe, bestehend aus Valproat, Risperdal, Lithobid, Zyprexa und Seroquel, einnimmt.
 
7. Verwendung nach Anspruch 6, wobei das pharmazeutisch annehmbare Salz ein Hydrochloridsalz ist.
 
8. Verwendung nach Anspruch 6 oder 7, wobei das pharmazeutisch annehmbare Salz von N,N-Dimethylimidocarbonimid-Diamid in einer Einheitsdosierungsform, ausgewählt aus der Gruppe, bestehend aus Depotfreisetzungsformen, Kontrollfreisetzungsformen, Verzögerungsfreisetzungsformen und Antwortfreisetzungsformen, vorliegt.
 
9. Verwendung nach Anspruch 8, wobei die Einheitsdosierungsform in einer Antwortfreisetzungsform vorliegt, wobei die Freisetzung des Hydrochloridsalzes von N,N-Dimethylimidocarbonimid-Diamid durch Nahrungsaufnahme ausgelöst ist.
 


Revendications

1. Composition pharmaceutique comprenant une quantité sure et efficace d'un actif psychotrope choisi dans le groupe comprenant le Valproate, le Risperdal, le Lithobid, le Zyprexa et le Seroquel, conjointement avec un actif contrôlant le poids comprenant un sel acceptable en pharmacie de metformine dans une quantité sûre et efficace pour minimiser la prise de poids provoquée par ledit actif psychotrope chez un patient prenant ledit actif psychotrope.
 
2. Composition selon la revendication 1, dans laquelle l'actif contrôlant le poids est le sel de chlorhydrate.
 
3. Composition selon la revendication 2, dans laquelle l'actif psychotrope est le Valproate.
 
4. Composition selon l'une quelconque des revendications 1 à 3, qui est élaborée pour une administration orale.
 
5. Composition selon la revendication 4, qui contient de 250 mg environ à 500 mg environ de Valproate, et de 250 mg environ à 500 mg environ de l'actif contrôlant le poids.
 
6. Utilisation d'un sel acceptable en pharmacie de metformine pour la préparation d'une composition destinée à être utilisée pour minimiser la prise de poids chez un patient prenant un actif psychotrope choisi dans le groupe comprenant le Valproate, le Risperdal, le Lithobid, le Zyprexa et le Seroquel.
 
7. Utilisation selon la revendication 6, dans laquelle le sel acceptable en pharmacie est le sel de chlorhydrate.
 
8. Utilisation selon l'une quelconque des revendications 6 ou 7, dans laquelle le sel acceptable en pharmacie de metformine se présente sous une forme galénique unitaire choisie dans le groupe comprenant des formes à libération prolongée, des formes à libération contrôlée, des formes à libération retardée et des formes à libération réactionnelle.
 
9. Utilisation selon la revendication 8, dans laquelle la forme galénique unitaire est une forme à libération réactionnelle, dans laquelle la libération de la metformine est déclenchée par l'ingestion de nourriture.